Azabicyclic esters of carbamic acids useful in therapy

ABSTRACT

A compound of formula ##STR1## X is O or S; Y is O or S; G and D are independently nitrogen or carbon with the proviso that no more than one of G, D, or E is nitrogen; E is N or C--R 4  ; R 1  is hydrogen or methyl; R 2  is hydrogen or fluoro; R 3  is hydrogen, halogen, C 1  to C 3  alkyl, --OR 5 , --CN, --CONH 2 , --CO 2  R 5 , --NR  5  R 6  or phenyl optionally substituted with one to three of the following substituents: halogen, C 1  to C 3  alkyl, --NO 2 , --CN, or --OCH 3  ; R 4  is hydrogen, halogen, C 1  to C 3  alkyl, --OR 5 , --CN, --CONH 2 , --CO 2  R 5 , --NR 5  R 6  or phenyl optionally substituted with one to three of the following substituents: halogen, C 1  to C 3  alkyl, --NO 2 , --CN, or --OCH 3  ; 
     or R 2  and R 3  or R 3  and R 4  may together represent a fused phenyl ring optionally substituted with one or two of the following substituents: halogen, C 1  to C 3  alkyl, --NO 2 , --CN, or --OCH 3  ; R 5  and R 6  are independently hydrogen or C 1  to C 3  alkyl; 
     or an enantiomer thereof, and pharmaceutically acceptable salts thereof, processes for preparing the, compositions containing them, and their use in therapy, especially in the treatment or prophylaxis of psychotic disorders and intellectual impairment disorders, as well as intermediates and use of intermediates in synthesis.

This is a continuation of application Ser. No. 08/836,143, filed Jun.13, 1997, now allowed.

FIELD OF THE INVENTION

This invention relates to novel azabicyclic esters of carbamic acids orpharmaceutically acceptable salts thereof, processes for preparing the,pharmaceutical compositions containing them and their use in therapy. Afurther object is to provide active compounds which are potent ligandsfor nicotinic acetylcholine receptors (nAChR's).

BACKGROUND OF THE INVENTION

The use of compounds which bind nicotinic acetylcholine receptors in thetreatment of a range of disorders involving reduced cholinergic functionsuch as Alzheimer's disease, cognitive or attention disorders, anxiety,depression, smoking cessation, neuroprotection, schizophrenia,analgesia, Tourette's syndrome, and Parkinson's disease has beendiscussed in "Nicotinic Acetylcholine Receptors: Molecular Biology,Chemistry, and Pharmacology", Chapter 5 in Annual Reports in MedicinalChemistry, Volume 30, pp. 41-50, Academic Press Inc., San Diego, Calif.(1995) and in "Neuronal Nicotinic Acetylcholine Receptors," Drug News &Perspectives, Volume 7, pp. 205-223 (1994).

U.S. Pat. No. 5,468,875 discloses N-alkylcarbamic acid1-azabicyclo[2.2.2]hept-3-yl esters which are centrally activemuscarinic agents useful in the treatment of Alzheimer's disease andother disorders.

N-(2-Alkoxyphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl esters aredisclosed in Pharmazie, 48, 465-466 (1993) along with their localanaesthetic activity.

N-Phenylcarbamic acid 1-azabicyclo[2.2.2]octan-3-yl esters substitutedat the ortho position on the phenyl ring are described as localanaesthetics in Acta Pharma. Suecica, 7, 239-246 (1970).

DISCLOSURE OF THE INVENTION

According to the invention we provide a compound of formula ##STR2##

X is O or S;

Y is O or S;

G and D are independently nitrogen or carbon with the proviso that nomore than one of G, D, or E is nitrogen;

E is N or C--R₄ ;

R₁ is hydrogen or methyl;

R₂ is hydrogen or fluoro;

R₃ is hydrogen, halogen, C₁ to C₃ alkyl, --OR₅, --CN, --CONH₂, --CO₂ R₅,--NR₅ R₆ or phenyl optionally substituted with one to three of thefollowing substituents: halogen, C₁ to C₃ alkyl, --NO₂, --CN, or --OCH₃;

R₄ is hydrogen, halogen, C₁ to C₃ alkyl, --OR₅, --CN, --CONH₂, --CO₂ R₅,--NR₅ R₆ or phenyl optionally substituted with one to three of thefollowing substituents: halogen, C₁ to C₃ alkyl, --NO₂, --CN, or --OCH₃;

or R₂ and R₃ or R₃ and R₄ may together represent a fused phenyl ringoptionally substituted with one or two of the following substituents:halogen, C₁ to C₃ alkyl, --NO₂, --CN, or --OCH₃ ;

R₅ and R₆ are independently hydrogen or C₁ to C₃ alkyl;

or an enantiomer thereof, and pharmaceutically acceptable salts thereof.

The compounds of formula I are potent ligands for nicotinicacetylcholine receptors.

Unless otherwise indicated, the term "C₁ -C₃ alkyl" referred to hereindenotes a straight or branched chain alkyl group having from 1 to 3carbon atoms or a cyclic alkyl group having 3 carbon atoms. Examples ofsuch groups are methyl, ethyl, n-propyl, i-propyl and cyclopropyl.

Unless otherwise indicated, the term "halogen" referred to hereindenotes fluoro, chloro, bromo or iodo.

Preferred compounds of the invention are compounds of formula I whereinA is formula II or IV; R₂ is hydrogen; X and Y are oxygen and G, D, andE are carbon.

Particularly preferred compounds of the invention include the following:

N-phenylcarbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

N-(4-bromophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

N-(4-methylphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

N-(4-methoxyphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

N-(3,4-dichlorophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

N-(4-cyanophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

N-phenylcarbamic acid 1-azabicyclo[2.2.2]heptan-3-yl ester;

N-(3-methoxyphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

N-phenylthiocarbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

N-(2-pyridyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

N-(1-naphthyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

N-phenylcarbamic acid (3R)-1-azabicyclo[2.2.2]octan-3-yl ester;

N-phenylcarbamic acid (3S)-1-azabicyclo[2.2.2]octan-3-yl ester;

N-(4-pyridyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

N-(m-biphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

N-(3-quinolinyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

More particularly preferred compounds of the invention include thefollowing:

N-(4-bromophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

N-(4-methylphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

N-(3,4-dichlorophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

N-(m-biphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester.

Other compounds of the invention include:

N-(2-fluorophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

N-(3-fluorophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

N-(4-fluorophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

N-(4-chlorophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

N-(3-chlorophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

N-(3-bromophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;

N-(3-chloro-4-fluorophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-ylester;

N-(4-chloro-3-fluorophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-ylester.

According to the invention, we further provide a process for thepreparation of compounds of formula I, and enantiomers thereof andpharmaceutically acceptable salts thereof.

Methods of Preparation

The compounds of formula I may be prepared according to the methods ofScheme 1, Scheme 2, and Scheme 3. In the reaction schemes and text thatfollow A, X, Y, G, D, E, R₁, R₂, R₃, R₄, R₅, and R₆, unless otherwiseindicated, are as defined above for formula I.

Method a) ##STR3##

Compounds of formula I may be prepared from the condensation of acompound of the formula VI with an isocyanate or isothiocyanate of theformula VII in an inert solvent in the presence of a catalyst. Suitableinert solvents include ethers, for example, diethyl ether,tetrahydrofuran or dioxane; acetonitrile, toluene,N,N-dimethylformamide, and N-methylpyrrolidin-2-one. Preferably thesolvent is acetonitrile, Suitable catalysts include tertiary amines suchas trialkylamines, for example, triethylamine;1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and1,5-diazabicyclo[4.3.0]non-5-ene (DBN), preferably triethylamine, ordibutyltin dilaurate. The reaction is usually conducted at a temperaturefrom about 25° C. to about 154° C., preferably about 25° C. to about 85°C. and at a pressure of about one to about three atmospheres, preferablyat ambient pressure (about one atmosphere).

Method b)

Alternatively, a compound of formula I can be prepared according toScheme 2. ##STR4##

A compound of formula I may be prepared from a compound of formula IXvia removal of the borane complex in a compound of formula IX using acidin an inert solvent. Suitable acids include mineral acids, for example,hydrochloric and hydrobromic acid; preferably hydrochloric acid.Suitable inert solvents include C₁ to C₄ alcohols and acetone;preferably acetone. The reaction is usually conducted at a temperatureof about -10° C. to about 50° C., preferably at about 0° C. to about 25°C.

Compounds of formula IX are novel and can be prepared from thecondensation of a compound of the formula VIII with an isocyanate orisothiocyanate of the formula VII in an inert solvent in the presence ofa catalyst. Suitable inert solvents and catalysts, and reactionconditions are the same as described under method (a) above, for thecondensation of the compound of formula VI with the compound of formulaVII.

Compounds of formula VIII, which is the borane complex of a compound offormula VI, are novel and may be prepared via the treatment of acompound of formula VI with an equimolar amount of borane intetrahydrofuran at about -10° C. to about 25° C., preferably at about 0°C. Extractive work up affords a compound of formula VIII which isgenerally used directly in the next step of the reaction sequence.

Compounds of formula VIII may be used as starting material incondensation reactions as well as starting material in a synthesis of aligand for nicotinic acetylcholine receptors.

Method c)

Alternatively, compounds of formula I can be prepared as outlined inScheme 3. ##STR5##

A compound of formula I may be prepared from the sequential reaction ofa compound of formula XI with a carbonyl donating compound of formulaXII, wherein Y is as defined above and L is a leaving group, forexample, chloride or imidazole, followed by immediate reaction of theresulting mixture with a compound of formula VI all done in the presenceof a basic catalyst in an inert solvent. The preferred compound offormula XII is carbonyldiimidazole. Suitable bases includetrialkylamines, for example, triethylamine;1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and1,5-diazabicyclo[4.3.0]non-5-ene (DBN); preferably triethylamine.Suitable inert solvents include N,N-dimethylformamide, acetonitrile,ethers, for example, tetrahydrofuran and dioxane, and acetone;preferably acetonitrile. The reaction is usually conducted at atemperature from about 25° C. to about 154° C., preferably about 25° C.to about 85° C. and at a pressure of about one to about threeatmospheres, preferably at ambient pressure (about one atmosphere).

Compounds of formulae VI, VII, XI and XII are either commerciallyavailable or may be prepared by methods known to one skilled in the art.

The compounds of the invention and intermediates may be isolated fromtheir reaction mixtures, and, if necessary, be further purified usingstandard techniques.

Acid addition salts of the compounds of formula I which may be mentionedinclude salts of mineral acids, for example, the hydrochloride andhydrobromide salts; and salts formed with organic acids such as formate,acetate, maleate, benzoate and fumarate salts.

Acid addition salts of compounds of formula I may be formed by reactingthe free base or a salt, enantiomer or protected derivative thereof,with one or more equivalents of the appropriate acid. The reaction maybe carried out in a solvent or medium in which the salt is insoluble orin a solvent in which the salt is soluble, for example, water, dioxane,ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents,which may be removed in vacuum or by freeze drying. The reaction may bea metathetical process or it may be carried out on an ion exchangeresin.

The compounds of formula I exist in tautomeric or enantiomeric forms,all of which are included within the scope of the invention. The variousoptical isomers may be isolated by separation of a racemic mixture ofthe compounds using conventional techniques, for example, fractionalcrystallization or chiral HPLC. Alternatively the individual enantiomersmay be made by reaction of the appropriate optically active startingmaterials under reaction conditions which will not cause racemization.

Intermediate compounds also exist in enantiomeric forms and may be usedas purified enantiomers, racemates or mixtures.

Utility

The compounds of formula I are agonists of nicotinic acetylcholinereceptors ["Nicotinic Acetylcholine Receptors: Molecular Biology,Chemistry, and Pharmacology", Chapter 5 in Annual Reports in MedicinalChemistry, Volume 30, pp. 41-50, Academic Press Inc., San Diego, Calif.(1995)]. While not being limited by theory, it is believed that agonistsof the α7 nAChR (nicotinic acetylcholine receptor) subtype should beuseful in the treatment or prophylaxis of psychotic disorders andintellectual impairment disorders, and have advantages over compoundswhich are, or are also, agonists of the α4 nAChR subtype. Therefore,compounds which are selective for the α7 nAChR subtype are preferred.The compounds of the invention are indicated as pharmaceuticals, inparticular in the treatment or prophylaxis of psychotic disorders andintellectual impairment disorders. Examples of psychotic disordersinclude schizophrenia, mania, manic depression and anxiety. Examples ofintellectual impairment disorders include Alzheimer's disease, learningdeficit, cognition deficit, attention deficit, memory loss, autism andAttention Deficit Hyperactivity Disorder. The compounds of the inventionmay also be useful as analgesics in the treatment of pain (includingchronic pain) and in the treatment or prophylaxis of Parkinson'sdisease, Huntington's disease, Tourette's syndrome, Amyotrophic LateralSclerosis and neurodegenerative disorders in which there is dysfunctionof the cholinergic system. The compounds may further be indicated forthe treatment or prophylaxis of jetlag, for use in inducing thecessation of smoking, and for the treatment or prophylaxis of nicotineaddiction (including that resulting from exposure to products containingnicotine).

It is also believed that compounds of formula I may be useful in thetreatment and prophylaxis of inflammatory bowel diseases, for example,ulcerative colitis.

Thus, according to a further aspect of the invention we provide acompound of formula I, or an enantiomer thereof, or a pharmaceuticallyacceptable salt thereof, for use as a pharmaceutical.

According to another aspect of the invention is the use of a compound offormula I, an enantiomer thereof or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for the treatment orprophylaxis of one of the above mentioned diseases or conditions; and amethod of treatment or prophylaxis of one of the above mentioneddiseases or conditions, which comprises administering a therapeuticallyeffective amount of a compound of formula I, or an enantiomer thereof ora pharmaceutically acceptable salt thereof, to a person suffering fromor susceptible to such a disease or condition.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administrationand the treatment desired. However, in general, satisfactory results areobtained when the compounds of the invention are administered at a dailydosage of from about 0.1 mg to about 20 mg per kg of animal body weight,preferably given in divided doses 1 to 4 times a day or in sustainedrelease form. For man, the total daily dose is in the range of from 5 mgto 1,400 mg, more preferably from 10 mg to 100 mg, and unit dosage formssuitable for oral administration comprise from 2 mg to 1,400 mg of thecompound optionally admixed with a solid or liquid pharmaceuticalcarrier or diluent.

Pharmaceutical compositions

The compounds of formula I and enantiomers thereof and pharmaceuticallyacceptable salts thereof may be used on their own, or in the form orappropriate medicinal compositions. Administration may be by, but is notlimited to, enteral (including oral, sublingual or rectal), intranasal,topical or parenteral routes. Conventional procedures for the selectionand preparation of suitable pharmaceutical compositions are describedin, for example, "Pharmaceuticals--The Science of Dosage Form Designs",M. E. Aulton, Churchill Livingstone, 1988.

According to the invention, there is provided a pharmaceuticalcomposition for treating or preventing a condition or disorder asexemplified above arising from dysfunction of nicotinic acetylcholinereceptor neurotransmission in a mammal, preferably a human, comprisingan amount of a compound of formula I, an enantiomer thereof or apharmaceutically acceptable salt thereof, effective in treating orpreventing such disorder or condition and optionally an inertpharmaceutically acceptable carrier.

According to a further aspect of the invention, there is provided apharmaceutical composition including preferably less than 80% by weightand more preferably less than 50% by weight of a compound of theinvention optionally in admixture with an inert pharmaceuticallyacceptable diluent or carrier.

Examples of diluents and carriers are: for tablets and dragees: lactose,starch, talc, stearic acid; for capsules: tartaric acid or lactose; forinjectable solutions: water, alcohols, glycerin, vegetable oils; forsuppositories: natural or hardened oils or waxes.

Compositions in a form suitable for oral, i.e. oesophageal,administration include tablets, capsules, syrups and dragees; sustainedrelease compositions include those in which the active ingredient isbound to an ion exchange resin which is optionally coated with adiffusion barrier to modify the release properties of the resin.

There is also provided a process for the preparation of such apharmaceutical composition which comprises mixing the ingredients.

Pharmacology

The pharmacological activity of the compounds of the invention may bemeasured in the tests set out below:

Test A--Assay for affinity to the α7 nAChR subtype

[¹²⁵ I]-α-Bungarotoxin (BTX) binding to rat hippocampal membranes

Rat hippocampi were homogenized in 20 volumes of cold homogenizationbuffer (HB: concentrations of constituents (mM):tris(hydroxymethyl)aminomethane 50; MgCl₂ 1; NaCl 120; KCl 5: pH 7.4).The homogenate was centrifuged for 5 minutes at 1000 g, the supernatantwas saved and the pellet re-extracted. The pooled supernatants werecentrifuged for 20 minutes at 12000 g, washed, and resuspended in HB.Membranes (30-80 μg) were incubated with 5 mM [¹²⁵ I]-α-BTX, 1 mg/mL BSA(bovine serum albumin), test drug, and either 2 mM CaCl₂ or 0.5 mM EGTA[ethylene glycol-bis(β-aminoethyl) ether] for 2 hours at 21° C., andthen filtered and washed 4 times over Whatman glass fibre filters(thickness C) using a Brandel cell harvester. Pretreating the filtersfor 3 hours with 1% (BSA/0.01% PEI (polyethyleneimine) in water wascritical for low filter blanks (0.07% of total counts per minute).Nonspecific binding was described by 100 μM (-)-nicotine, and specificbinding was typically 75%.

Test B--Assay for affinity to the α4 nAChR subtype

[³ H]-(-)-Nicotine binding.

Using a procedure modified from Martino-Barrows and Kellar, Mol.Pharma., 31, 169-174, (1987), the contents of which are herebyincorporated herein by reference, rat brain (cortex and hippocampus) washomogenized as in the [¹²⁵ I]-α-BTX binding assay, centrifuged for 20minutes at 12000 g, washed twice, and then resuspended in HB containing100 μM diisopropyl fluorophosphate. After 20 minutes at 4° C., membranes(approximately 0.5 mg) were incubated with 3 nM [³ H]-(-)-nicotine, testdrug, 1 μM atropine, and either 2 mM CaCl₂ or 0.5 mM EGTA for 1 hour at4° C., and then filtered over Whatman glass fibre filters (thickness B)(pretreated for 1 hour with 0.5% PEI) using a Brandel cell harvester.Nonspecific binding was described by 100 μM carbachol, and specificbinding was typically 84%.

Binding data analysis for Tests A and B

IC₅₀ values and pseudo Hill coefficients (n_(H)) were calculated usingthe non-linear curve fitting program ALLFIT [A. DeLean, P. J. Munson andD. Rodbard, Am J. Physiol., 235, E97-E102 (1977)]. Saturation curveswere fitted to a one site model, using the non-linear regression programENZFITTER [R. J. Leatherbarrow (1987)], yielding K_(D) values of 1.67and 1.70 nM for the [¹²⁵ I]-α-BTX and [³ H]-(-)-nicotine ligandsrespectively. K_(i) values were estimated using the generalCheng-Prustoff equation:

    K.sub.i -[IC.sub.50 ]/((2+([ligand]/[K.sub.D ]).sup.n).sup.l/n -1)

where a value of n=1 was used whenever n_(H) <1.5 and a value n=2 wasused when n_(H) ≧1.5. Samples were assayed in triplicate andreproducibility was typically ±5%. K_(i) values were determined using 6or more drug concentrations. The compounds of the invention arecompounds with binding affinities (K_(i)) of less than 1000 nM in eitherTest A or Test B, indicating that they are expected to have usefultherapeutic activity.

When compared with other compounds, the compounds of the invention havethe advantage that they may be less toxic, be more efficacious, belonger acting, have a broader range of activity, be more potent, be moreselective for the α7 nAChR subtype, produce fewer side effects, are moreeasily absorbed or have other useful pharmacological properties.

Experimental part

The following Examples illustrate the preparation of compounds of thepresent invention but in no way limit the scope of the invention.

General Experimental Procedures

Commercial reagents were used without further purification. NMR data arereported in parts per million (δ), and are referenced to the chemicalshift of tetramethylsilane or the deuterium lock from the samplesolvent, and were obtained on either a Bruker 250 MHz or Bruker 500 MHzinstrument. Chromatography (silica gel filtration) utilized 230-400 meshsilica gel. Room temperature refers to 20-25° C.

EXAMPLE 1

General Synthesis of N-Arylcarbamic acid esters, N-Heteroarylcarbamicacid esters, N-Arylthiocarbamic acid esters and N-Heteroarylthiocarbamicacid esters

A mixture of the azabicycloalkyl alcohol (formula VI, 2.00 mmol), theappropriate isocyanate or isothiocyanate (formula VII, 2.00 mmol),triethylamine (20 mol %), and acetonitrile (10 mL) was heated at refluxunder nitrogen for 2 to 8 hours, unless otherwise noted. Then, absolutemethanol (0.10 mL, 2.5 mmol) was added, and reflux was continued for 1hour. The resulting reaction solution was cooled to room temperature,and any precipitated solid was isolated via filtration. If the solid wasnot the pure carbamic acid ester, additional purification could beachieved by recrystallization or column chromatography using silica gel(approximately 50 g) and elution with 9:1:0.1 methylenechloride/methanol/ammonium hydroxide to afford the pure carbamic acidester.

Following this procedure the following compounds were prepared:

A. N-(4-Bromophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester

3-Quinuclidinol and 4-bromophenyl isocyanate were used. Filtration ofthe precipitated solid from the cooled reaction mixture afforded thetitle compound (60%) as a white solid: mp 217.5-219.5° C.; FAB LRMS ^(m)/z (relative intensity, %) 328 (16), 327 ([MH⁺ with Br⁸¹ ], 100), 326(16), 325 ([MH⁺ with Br⁷⁹ ], 100).

B. N-(4-Methylphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester

3-Quinuclidinol and 4-tolyl isocyanate were used. Filtration of theprecipitated solid from the cooled reaction mixture afforded the titlecompound (93%) as a white solid: mp 186.0-187.5° C.; FAB LRMS ^(m) /z(relative intensity, %) 262 (21), 261 ([MH⁺ ], 100).

C. N-(3,4-Dichlorophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3ylester

3-Quinuclidinol and 3,4-dichlorophenyl isocyanate were used. Filtrationof the precipitated solid from the cooled reaction mixture afforded thetitle compound (60%) as a white solid: mp 181.0-184.0° C.; FAB LRMS ^(m)/z (relative intensity, %) 319 ([MH⁺ with two Cl³⁷ ], 13), 318 (11), 317([MH⁺ with one Cl³⁷ ], 71), 316 (18), 315 ([MH⁺ with two Cl³⁵ ], 100).

D. N-(4-Methoxyphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3yl ester

3-Quinuclidinol and 4-methoxyphenyl isocyanate were used. The solidwhich precipitated from the reaction mixture was recrystallized fromethyl acetate to afford the title compound (43%) as a white solid: mp159.5-160.5° C.; FAB LRMS ^(m) /z (relative intensity, %) 277 (MH⁺ 1,16), 110 (100).

E. N-(2-Fluorophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester

3-Quinuclidinol and 2-fluorophenyl isocyanate were used. The reactionsolution was evaporated under reduced pressure, and the residual solidwas recrystallized from ethyl acetate to afford the title compound (79%)as a white solid: mp 124.0-126.0° C.; FAB LRMS ^(m) /z (relativeintensity %) 265 (MH⁺, 22), 110 (100).

F. N-(3-Methoxyphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester

3-Quinuclidinol and 3-methoxyphenyl isocyanate were used. The reactionsolution was evaporated under reduced pressure, and the residual solidwas recrystallized from ethyl acetate to afford the title compound (60%)as a white solid: mp 130.5-132.0° C.; FAB LRMS ^(m) /z (relativeintensity, %) 278 (18), 277 (MH⁺, 100).

G. N-Phenylthiocarbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester

3-Quinuclidinol and phenyl isothiocyanate were used. The reactionsolution was heated at reflux under nitrogen for 6 days. The reactionsolution was chromatographed using silica gel and elution with 10%methanol in methylene chloride followed by a solution of methylenechloride/methanol/ammonium hydroxide (9:1:0.1) to afford a white foam.This foam was dissolved in ethyl acetate/ether (1:9, 10 mL/g of foam),and the resulting cloudy solution was filtered through diatomaceousearth. The resultant filtrate was evaporated under reduced pressure, andthe residual foam was crystallized from ethyl acetate/hexanes (1:3) toafford the title compound (29%) as a white solid: mp 132.0-133.0° C.;FAB LRMS ^(m) /z (relative intensity, %) 263 (MH⁺, 14), 110 (100).

EXAMPLE 2

General Synthesis of N-Arylcarbamic acid esters, N-Heteroarylcarbamicacid esters, N-Arylthiocarbamic acid esters and N-Heteroarylthiocarbamicacid esters.

To a stirred solution of the appropriate aniline (formula XI, 10.00mmol) and triethylamine (20 mol %) in anhydrous acetonitrile (50 mL) wasadded carbonyldiimidazole (1.622 g, 10.00 mmol), and the resultingreaction mixture was stirred at room temperature under nitrogenovernight (16 hours). Then, an alcohol of formula VI (10.00 mmol) wasadded, and the resulting reaction mixture was heated at reflux undernitrogen for 48 hours. The resulting reaction mixture was evaporatedunder reduced pressure, and the residue was partitioned between ethylacetate (150 mL) and saturated aqueous sodium carbonate (150 mL). Theaqueous layer was removed, and the ethyl acetate layer was washed with asaturated aqueous sodium carbonate solution (4×100 mL). The ethylacetate layer was dried (MgSO₄), and evaporated under reduced pressure.The residue was chromatographed using 5 to 20% methanol saturated withammonia in chloroform to afford the title compound. If necessary,recrystallization can provide more pure title compound.

Following this procedure the following compounds were prepared:

A. N-(4-Cyanophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester

3-Quinuclidinol and 4-aminobenzonitrile were used. Chromatographyafforded a residue which was triturated in ethyl acetate to afford thetitle compound (11%) as a white solid: mp 180.0-182.0° C.; FAB LRMS ^(m)/z (relative intensity, %) 273 (17), 272 (MH⁺, 100), 110 (52).

B. N-(2-Pyridyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester

3-Quinuclidinol and 2-aminopyridine were used. The title compound wasisolated as a white solid (8%): mp 166-167° C.; FAB LRMS ^(m) z 248(MH⁺).

EXAMPLE 3

General Synthesis of N-Arylcarbamic acid 1-azabicyclo[2.2.2]heptan-3-ylesters and N-Arylcarbamic acid 1-azabicyclo[2.2.2]octan-3-yl esters

To an ice cold suspension of the appropriate azabicycloalkyl alcohol(formula VI, 13.3 mmol) in tetrahydrofuran (15 mL) was dropwise addedover 30 minutes borane-tetrahydrofuran complex (1.0M in THF, 13.3 mL,13.3 mmol). The resulting solution was warmed up to room temperature for1 hour. A few drops of water were added followed by brine solution (30mL) and ethyl acetate (30 mL). the organic layer was separated, theaqueous layer extracted with ethyl acetate (30 mL), and the combinedextracts were dried (MgSO₄) and evaporated under reduced pressure togive a borane complex of the appropriate azabicycloalkyl alcohol. Asolution of the borane complex (2.48 mmol), an aryl isocyanate (formulaVII, 3.0 mmol), and triethylamine (0.1 mL) in anhydrous tetrahydrofuran(5 mL) was stirred under nitrogen at room temperature for 24 hours andthen evaporated under reduced pressure. The residue was treated withacetone (5 mL) and 2.5N HCl (3 mL) and stirred at room temperatureovernight. The mixture was then evaporated under reduced pressure, andthe resulting residue was further purified as required.

Following this procedure the following compounds were prepared:

A. N-Phenylcarbamic acid 1-azabicyclo[2.2.1]heptan-3-yl ester

1-Azabicyclo[2.2.1]heptan-3-endo-ol [Helv. Chim Acta, 75, 507 (1992]andphenyl isocyanate were used. The residual solid resulting from the abovedescribed procedure was recrystallized twice from isopropanol to affordthe title compound (56%) as a white crystalline solid: FAB LRMS ^(m) /z(relative intensity, %) 233 ([MH⁺ ], 100). Anal. calcd. for C₁₃ H₁₇ N₂O₂ Cl: C, 58.10; H, 6.37; N, 10.42. Found C, 58.11; H, 6.40; N, 10.42%.

B. N-Phenylcarbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester

1-Azabicyclo[2.2.2]octan-3-ol and phenyl isocyanate were used. Theresidual solid resulting from the above described procedure was purifiedvia column chromatography eluting with a 1:10 ratio ofmethanol:chloroform to afford the title compound (86%) as a white solid:NMR (CDCl₃) δ7.60-7.0 (m, 5H, Ph), 4.81 (m, 1H, CH--OCO), 3.27 (m, 1H,one of NCH₂ C--O), 2.9 (m, 5H, N(CH₂)₂ and one of NCH₂ C--O), 2.1 (m,1H, methine at C₄), 2.05-1.30 (m, 4H, CH₂ at C₅ and C₈); FAB LRMS ^(m)/z (relative intensity, %) 247 ([MH⁺ ], 100).

C. N-(1-Naphthyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester

1-Naphthylisocyanate and 3-quinuclidinol were used. The title compoundwas isolated as a white solid (34%): mp 186-188° C.; FAB LRMS ^(m) /z297 (MH⁺).

EXAMPLE 4

N-Phenylcarbamic acid (3R)-1-azabicyclo[2.2.2]octan-3-yl ester

A solution of (3R)-(-)-quinuclidin-3-ol (0.30 g, 2.36 mmol) [M.Langlois, C. Meyr, and J. L. Soulier, Synth. Comm., 23, 1895-1911(1992)], triethylamine (0.07 mL, 20 mol %) and phenyl isocyanate (0.28mL, 2.58 mmol, 1.1 equivalents) in anhydrous acetonitrile (5 mL) washeated at reflux under nitrogen for 46 hours. Water (25 mL) was added,and the resulting aqueous mixture was extracted with ethyl acetate (2×25mL). The resulting extracts were combined, dried (MgSO₄), and evaporatedunder reduced pressure. The resulting foam was crystallized using ethylacetate/hexanes (2:1) to afford a white solid (0.42 g). this white solidwas placed in 1N HCl (20 mL), and the resulting aqueous mixture wasextracted with ethyl acetate (2×25 mL). These organic extracts werediscarded. The aqueous solution was made basic (pH>13) with solid Na₂CO₃ and aqueous 10% KOH. The resulting aqueous solution was extractedwith ethyl acetate (2×25 mL), and these extracts were combined, dried(MgSO₄), and evaporated under reduced pressure. The resulting solid wastriturated in ether/hexanes (3:1) to afford the title compound (0.100 g,17%) as a white, crystalline solid: mp 131.0-132.0° C.; FAB LRMS ^(m) /z(relative intensity, %) 247 (MH⁺, 41), 110 (100); [α]²² _(D) =+7.5°(c=0.9, MeOH).

EXAMPLE 5

N-Phenylcarbamic acid (3S)-1-azabicyclo[2.2.2]octan-3-yl ester

A solution of (3S-(+)-quinuclidin-3-ol (0.50 g, 3.93 mmol) [M. Langlois,C. Meyer, and J. L. Soulier, Synth. Comm., 23, 1895-1911 (1992)], phenylisocyanate (0.47 mL, 4.32 mmol, 1.1 equivalents), and dibutyltindilaurate (0.013 mL, 0.08 mmol) in anhydrous toluene (20 mL) was heatedat reflux under nitrogen for 1 hour. The resulting reaction mixture wasevaporated under reduced pressure, and the resulting solid was placed in1N HCl (25 mL). The resulting aqueous mixture was extracted with ethylacetate (2×25 mL), basified to pH 10 with Na₂ CO₃, and extracted withchloroform (3×50 mL). The chloroform extracts were combined, dried(MgSO₄), and evaporated under reduced pressure. The resulting solid wasrecrystallized using toluene (5 mL) to afford the title compound (0.875g, 90%) as a white solid: mp 129.0-130.0° C.; FAB LRMS ^(m) /z (relativeintensity, %) 247 (MH⁺, 39), 110 (100); [α]²² _(D) =-7.5° (c=1.0, MeOH).

EXAMPLE 6

N-(4-Pyridyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester

3-Quinuclidinol and 4-(2,6-dicloropyridyl)isocyanate were used tosynthesis N-[4-(2,6-dichloropyridyl)]carbamic acid1-azabicyclo[2.2.2]octan-3-yl ester following the method described inExample 3. A solution of N-[4-(2,6-dichloropyridyl)]carbamic acid1-azabicyclo[2.2.2]octan-3-yl ester (0.5 g, 1.58 mmol), palladiumchloride (0.3 g) and potassium acetate (0.32 g) in methanol (10 mL) wasshaken under a hydrogen atmosphere (3 atm). The reaction mixture wasfiltered, and the filtrate was evaporated under reduced pressure. Theresidue was partitioned between chloroform and saturated sodiumcarbonate and separated. The aqueous layer was further extracted withchloroform. The chloroform extracts were combined, dried (MgSO₄) andevaporated to give a solid. This solid was triturated in ether to affordthe title compound (69%) as a solid: mp 149-151° C.; FAB LRMS ^(m) /z248 (MH⁺).

EXAMPLE 7

General Method for Preparing N-Arylcarbamic acid esters andN-Heteroarylcarbamic acid esters

To a stirred solution of 3-quinuclidinol (10 mmol) in anhydrouschloroform (40 mL) and at 0° C. was added 1.93M phosgene in toluene (5.2mL, 10 mmol) under nitrogen, and the resulting mixture was stirred at 0°C. for 1 hour to give a very fine suspension. The appropriate arylamineor heteroarylamine (10 mmol) was then added, followed by triethylamine(11 mmol). The cooling bath was removed 30 minutes later and theresulting reaction mixture was stirred at room temperature overnight.Chloroform (40 mL) was added to the reaction mixture followed bysaturated aqueous sodium bicarbonate until the mixture was basic. Thechloroform layer was separated. The aqueous layer was further extractedwith chloroform (30 mL). The organic layers were combined, dried (MgSO₄)and evaporated under reduced pressure. The residue was purified bycolumn chromatography eluting with 3 to 5% methanol saturated withammonia in chloroform to give the pure carbamic acid ester.

Following this procedure the following compounds were synthesized:

A. N-(m-Biphenyl)carbamic acid 1-Azabicyclo[2.2.2]octan-3-yl ester

3-Quinuclidinol and m-aminobiphenyl were used to give the title compound(26%) as white crystals: mp 203-204.5° C.; FAB LRMS ^(m) /z 323 (MH⁺).

B. N-(3-Quinolinyl)carbamic acid 1-azabicyclo[2.2.2]octan-3yl ester

3-Quinuclidinol and 3-aminoquinoline were used to give the titlecompound (46%) as a solid: mp 135-137° C.; FAB LRMS ^(m) /z 298 (MH⁺).

What is claimed is:
 1. A method of treatment or prophylaxis ofParkinson's disease, Huntington's disease, Tourette's syndrome,Amyotropic Lateral Sclerosis or neurodegenerative disorders in whichthere is dysfunction of the cholinergic system, which comprisesadministering a therapeutically effective amount of a compound offormula ##STR6## wherein: A is ##STR7## X is O or S; Y is O or S;G and Dare independently nitrogen or carbon with the proviso that no more thanone of G, D, or E is nitrogen; E is N or C--R₄ ; R₁ is hydrogen ormethyl; R₂ is hydrogen or fluoro; R₃ is hydrogen, halogen, C₁ to C₃alkyl, --OR₅, --CN, --CONH₂, --CO₂ R₅, --NR₅ R₆ or phenyl optionallysubstituted with one to three of the following substituents: halogen, C₁to C₃ alkyl, --NO₂, --CH, or --OCH₃ ; R₄ is hydrogen, halogen, C₁ to C₃alkyl, --OR₅, --CN, --CONH₂, --CO₂ R₅, --NR₅ R₆ or phenyl optionallysubstituted with one to three of the following substituents: halogen, C₁to C₃ alkyl, --NO₂, --CN, or --OCH₃ ; or R₂ and R₃ or R₃ and R₄ maytogether represent a fused phenyl ring optionally substituted with oneor two of the following substituents: halogen, C₁ to C₃ alkyl, --NO₂,--CN, or --OCH₃ ; R₅ and R₆ are independently hydrogen or C₁ to C₃alkyl; or an enantiomer thereof, or a pharmaceutically acceptable saltthereof.
 2. A method of treatment or prophylaxis of jetlag, cessation ofsmoking, nicotine addition including that resulting from exposure toproducts containing nicotine, pain, and inflammatory bowel diseaseswhich comprises administering a therapeutically effective amount of acompound of formula ##STR8## wherein: A is ##STR9## X is O or S; Y is Oor S;G and D are independently nitrogen or carbon with the proviso thatno more than one of G, D, or E is nitrogen; E is N or C--R₄ ; R₁ ishydrogen or methyl; R₂ is hydrogen or fluoro; R₃ is hydrogen, halogen,C₁ to C₃ alkyl, --OR₅, --CN, --CONH₂, --CO₂ R₅, --NR₅ R₆ or phenyloptionally substituted with one to three of the following substituents:halogen, C₁ to C₃ alkyl, --NO₂, --CN, or --OCH₃ ; R₄ is hydrogen,halogen, C₁ to C₃ alkyl, --OR₅, --CN, --CONH₂, --CO₂ R₅, --NR₅ R₆ orphenyl optionally substituted with one to three of the followingsubstituents: halogen, C₁ to C₃ alkyl, --NO₂, --CN, or --OCH₃ ; or R₂and R₃ or R₃ and R₄ may together represent a fused phenyl ringoptionally substituted with one or two of the following substituents:halogen, C₁ to C₃ alkyl, --NO₂, --CN, or --OCH₃ ; R₅ and R₆ areindependently hydrogen or C₁ to C₃ alkyl; or an enantiomer thereof, or apharmaceutically acceptable salt thereof.
 3. A compound of formula IX##STR10## wherein A is ##STR11## X is O or S; Y is O or S;G and D areindependently nitrogen or carbon with the proviso that no more than oneof G, D, or E is nitrogen; E is N or C--R₄ ; R₁ is hydrogen or methyl;R₂ is hydrogen or fluoro; R₃ is hydrogen, halogen, C₁ to C₃ alkyl,--OR₅, --CN, --CONH₂, --CO₂ R₅, --NR₅ R₆ or phenyl optionallysubstituted with one to three of the following substituents: halogen, C₁to C₃ alkyl, --NO₂, --CN, or --OCH₃ ; R₄ is hydrogen, halogen, C₁ to C₃alkyl, --OR₅, --CN, --CONH₂, --CO₂ R₅, --NR₅ R₆ or phenyl optionallysubstituted with one to three of the following substituents: halogen, C₁to C₃ alkyl, --NO₂, --CN, or --OCH₃ ; or R₂ and R₃ or R₃ and R₄ maytogether represent a fused phenyl ring optionally substituted with oneor two of the following substituents: halogen, C₁ C₃ alkyl, --NO₂, --CN,or --OCH₃ ; R₅ and R₆ are independently hydrogen or C₁ to C₃ alkyl; oran enantiomer thereof.